Figure 7

β-amyloid signals through microglial MAC1 receptor and PI3K to PHOX. Microglia exposed to Aβ exhibit a respiratory burst leading to the release of superoxide anion (O₂ ^-). Release of superoxide is mediated in part through the Aβ cell surface receptor MAC1. Aβ engagement of MAC1 receptor leads to the initiation of complex signaling events mediated by PI3K activation and PIP₃ production, which leads to AKT phosphorylation and activation of PDK. Activation of these signaling cascades is linked to the activation of PHOX. PHOX plays an essential role in innate immunity by catalyzing the formation of superoxide. PHOX consists of two integral membrane proteins, p22^phoxand gp91^phox, which together form a heterodimeric flavoprotein known as cytochrome b558. In addition, there are four cytosolic components p47^phox, p67^phox, p40^phox, and the small G-protein Rac. As an important component for PHOX activation, the GDP/GTP exchange on Rac-1 is reported to be a point of possible PI3K intervention. PIP₃ is reported to bind to p47^phoxand p40^phox, and mediates their phosphorylation[46]; PI3K signaling pathway may also sometimes be involved in PKC activation, thus play an important role in the phosphorylation of p47^phox. The cytosolic components then translocate to the membrane where they form a complex with cytochrome b558. The oxidase complex then initiates electron flow and generation of superoxide through the NADPH-derived electron reduction by the flavocytochrome. These findings suggest that MAC1 and PI3K are involved in upstream signaling cascades responsible for activating PHOX assembly and microglia in response to Aβ.